Autoantibody-positive individuals who are at risk for IDDM already have an advanced autoimmune process. It is therefore crucial to develop therapeutics that are effective late in the disease process. The ability of traditional strategies based on using beta-cell autoantigens (such as the insulin B chain, GAD, and HSP) to prime regulatory responses which suppress the spontaneous autoimmune process in NOD mice declines dramatically as the disease progresses in these mice, presumably because recruitment of T cells into the autoimmune process depletes the pool of uncommitted autoantigen-reactive T cells that are available for priming toward a regulatory phenotype. In contrast, it is possible that, even at late stages of pre-IDDM, large pools of uncommitted T cells exist against beta-cell antigenic determinants which are not targets of the autoimmune response (i.e., neglected target tissue antigens = NTTA). Therefore, a new therapeutic approach could be developed based on the administration of NTTAs which are capable of eliciting regulatory responses even late in the disease process. This possibility is supported by preliminary data showing that the administration of NTTAs is superior to the traditional approach of administering beta-cell autoantigen determinants (i.e., targeted antigens) in inhibiting IDDM in adult NOD mice. Furthermore, NTTA administration in IFA induces polarized Th2 regulatory responses while autoantigen administration can induce both Th1 pro-inflammatory and Th2 regulatory responses. Thus, the NTTA approach may be a safer immunotherapeutic strategy. This application has four specific aims using NOD mice: To determine the relative frequency of T cell precursors to targeted and neglected beta-cell antigens. The hypothesis is that uncommitted T cells against targeted autoantigens decline in frequency as the autoimmune process progresses while the pool of uncommitted T cells against NTTAs remains stable. To examine the factors underlying the hierarchy of beta-cell antigenic determinants. The hypothesis is that NTTAs are cryptic determinants. To determine the mechanisms underlying the efficacy of NTTA-based immunotherapeutics. The hypothesis is that NTTAs have a greater capacity to activate NTTA-specific anti-inflammatory responses, which spread to other beta-cell antigens such as the targeted autoantigens. To examine the safety of NTTA vs. targeted beta-cell autoantigens (beta-CAA) immunotherapies. The hypothesis is that NTTA immunotherapy carries a lower risk of inducing pro-inflammatory autoimmune responses than beta-CAA-based therapy.